1. Field of the Invention:
This invention relates to methods for the preparation and isolation of the specified hematoporphyrin derivatives (HPD) and methods for their use in localization, photosensitization and treatment of tumors. More particularly, this invention relates to methods for the preparation and use of new hematoporphyrin derivatives containing ester-linked chlorins.
2. Background of the Prior Art:
Complex mixtures of porphyrins derived from hematoporphyrin have been cited by Lipson and Baldes as having the ability to localize in neoplastic tissues. See Lipson and Baldes, "Hematoporphyrin Derivative: A New Aid Endoscopic Detection of Malignant Disease", 42 Journal of Thurasic Cardiovascular Surgery, 1961, pp 623-629. The resulting photosensitization can catalyze highly selective forms of tumor eradication if a sufficient light flux is provided as reported by Dougherty in Porphyrin Localization and Treatment of Tumors, pp 75-87 (1984); Kessel in "Hematoporphyrin and HPD: Photophysics, Photochemistry and Phototherapy", Photochemical Photobiology, Vol. 39, pp 851-859 (1984); and Land in "Porphyrin Phototherapy of Human Cancer", 46, International Journal of Radiation Biology, pp 219-223 (1984).
An inherent limitation associated with this form of photodynamic therapy is that the production of photodamage in tumor cells requires irradiation of porphyrin-loaded tissues with light at a wavelength that corresponds to one of the porphyrin absorption bands, i.e., 500, 567 and 630 nm. Tissue transparency is known to increase with increasing wave length. Thus, clinical photodynamic tumor eradication preferably takes place at the higher wave lengths such as 630 nm; the weakest of the porphyrin absorption bands.
Thus, as reported in Doiron et al, "Light Dosimetry in Tissue: Application to Photoradiation Therapy" in Porphyrin Photosensitization, pp 63-76 (1983) and in "Photophysics and Instrumentation for Porphyrin Detection and Activation" in Porphyrin Localization and Treatment of Tumors pp 41-73 (1984), to date photodynamic tumor eradication has been limited by two factors. First, the optical properties of tissues results in substantial scattering and absorption of light. Second, light at 630 nm exhibits weak photoactivating efficiency. It has been found that photodynamic therapy is most effective only when small lesions are treated. See Hayata et al, "Hematoporphyrin Derivative and Photoradiation Therapy in Early State Lung Cancer, Laser Surgery Medicine, Vol. 4, pp 39-47 (1984). This phenomenon is related to the decreased photodynamic effect as a function of tissue depth.
Thus, it is highly desirable to devise a tumor localizing photosensitizer drug with a strong absorption in the red spectrum, thereby enhancing the photodynamic toxicity.
It is also desirable that the drug be highly tumor-selective and that the drug be capable of emitting suitable readable chemical characteristics such as fluorescence which will aid in delineating malignancy and in diagnosis.
It is also desirable that a method be provided for preparation and isolation of this drug.